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Role of Cell Cycle Proteins in CNS Injury

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Abstract

Following trauma or ischemia to the central nervous system (CNS), there is a marked increase in the expression of cell cycle-related proteins. This up-regulation is associated with apoptosis of post-mitotic cells, including neurons and oligodendrocytes, both in vitro and in vivo. Cell cycle activation also induces proliferation of astrocytes and microglia, contributing to the glial scar and microglial activation with release of inflammatory factors. Treatment with cell cycle inhibitors in CNS injury models inhibits glial scar formation and neuronal cell death, resulting in substantially decreased lesion volumes and improved behavioral recovery. Here we critically review the role of cell cycle pathways in the pathophysiology of experimental stroke, traumatic brain injury and spinal cord injury, and discuss the potential of cell cycle inhibitors as neuroprotective agents.

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References

  1. Cernak I, Stoica B, Byrnes KR et al (2005) Role of the cell cycle in the pathobiology of central nervous system trauma. Cell Cycle 4:1286–1293

    PubMed  CAS  Google Scholar 

  2. Di Giovanni S, Knoblach SM, Brandoli C et al (2003) Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol 53:454–468

    Article  PubMed  CAS  Google Scholar 

  3. Greene LA, Biswas SC, Liu DX (2004) Cell cycle molecules and vertebrate neuron death: E2F at the hub. Cell Death Differ 11:49–60

    Article  PubMed  CAS  Google Scholar 

  4. Hayashi T, Sakurai M, Abe K et al (1999) DNA fragmentation precedes aberrant expression of cell cycle-related protein in rat brain after MCA occlusion. Neurol Res 21:695–698

    PubMed  CAS  Google Scholar 

  5. Kato H, Takahashi A, Itoyama Y (2003) Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat. Brain Res Bull 60:215–221

    Article  PubMed  CAS  Google Scholar 

  6. Kaya SS, Mahmood A, Li Y et al (1999) Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res 818:23–33

    Article  PubMed  CAS  Google Scholar 

  7. Padmanabhan J, Park DS, Greene LA et al (1999) Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J Neurosci 19:8747–8756

    PubMed  CAS  Google Scholar 

  8. Strazza M, Luddi A, Brogi A et al (2004) Activation of cell cycle regulatory proteins in the apoptosis of terminally differentiated oligodendrocytes. Neurochem Res 29:923–931

    Article  PubMed  CAS  Google Scholar 

  9. Wiessner C, Brink I, Lorenz P et al (1996) Cyclin D1 messenger RNA is induced in microglia rather than neurons following transient forebrain ischaemia. Neuroscience 72:947–958

    Article  PubMed  CAS  Google Scholar 

  10. Di Giovanni S, Movsesyan V, Ahmed F et al (2005) Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci USA 102:8333–8338

    Article  PubMed  CAS  Google Scholar 

  11. Verdaguer E, Jimenez A, Canudas AM et al (2004) Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment. J Pharmacol Exp Ther 308:609–616

    Article  PubMed  CAS  Google Scholar 

  12. Wang F, Corbett D, Osuga H et al (2002) Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat. J Cereb Blood Flow Metab 22:171–182

    Article  PubMed  CAS  Google Scholar 

  13. Kruman II, Wersto RP, Cardozo-Pelaez F et al (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41:549–561

    Article  PubMed  CAS  Google Scholar 

  14. Otsuka Y, Tanaka T, Uchida D et al (2004) Roles of cyclin-dependent kinase 4 and p53 in neuronal cell death induced by doxorubicin on cerebellar granule neurons in mouse. Neurosci Lett 365:180–185

    Article  PubMed  CAS  Google Scholar 

  15. Park DS, Obeidat A, Giovanni A et al (2000) Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment. Neurobiol Aging 21:771–781

    Article  PubMed  CAS  Google Scholar 

  16. Wen Y, Yang S, Liu R et al (2004) Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer’s disease-like tauopathy in female rats. J Biol Chem 279:22684–22692

    Article  PubMed  CAS  Google Scholar 

  17. Love S (2003) Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 27:267–282

    Article  PubMed  CAS  Google Scholar 

  18. Okano HJ, Pfaff DW, Gibbs RB (1993) RB and Cdc2 expression in brain: correlations with 3H-thymidine incorporation and neurogenesis. J Neurosci 13:2930–2938

    PubMed  CAS  Google Scholar 

  19. Nguyen MD, Mushynski WE, Julien JP (2002) Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 9:1294–1306

    Article  PubMed  CAS  Google Scholar 

  20. Wartiovaara K, Barnabe-Heider F, Miller FD et al (2002) N-myc promotes survival and induces S-phase entry of postmitotic sympathetic neurons. J Neurosci 22:815–824

    PubMed  CAS  Google Scholar 

  21. Boonstra J (2003) Progression through the G1-phase of the on-going cell cycle. J Cell Biochem 90:244–252

    Article  PubMed  CAS  Google Scholar 

  22. Sherr CJ (1993) Mammalian G1 cyclins. Cell 73:1059–1065

    Article  PubMed  CAS  Google Scholar 

  23. Nishitani H, Lygerou Z (2002) Control of DNA replication licensing in a cell cycle. Genes Cells 7:523–534

    Article  PubMed  CAS  Google Scholar 

  24. Obaya AJ, Sedivy JM (2002) Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci 59:126–142

    Article  PubMed  CAS  Google Scholar 

  25. Fischer PM, Endicott J, Meijer L (2003) Cyclin-dependent kinase inhibitors. Prog Cell Cycle Res 5:235–248

    PubMed  Google Scholar 

  26. Coqueret O (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13:65–70

    Article  PubMed  CAS  Google Scholar 

  27. Sherr CJ (1995) Mammalian G1 cyclins and cell cycle progression. Proc Assoc Am Physicians 107:181–186

    PubMed  CAS  Google Scholar 

  28. Kitagawa M, Higashi H, Jung HK et al (1996) The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. Embo J 15:7060–7069

    PubMed  CAS  Google Scholar 

  29. Liu DX, Greene LA (2001) Regulation of neuronal survival and death by E2F-dependent gene repression and derepression. Neuron 32:425–438

    Article  PubMed  CAS  Google Scholar 

  30. Sears RC, Nevins JR (2002) Signaling networks that link cell proliferation and cell fate. J Biol Chem 277:11617–11620

    Article  PubMed  CAS  Google Scholar 

  31. Osuga H, Osuga S, Wang F et al (2000) Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci USA 97:10254–10259

    Article  PubMed  CAS  Google Scholar 

  32. Li LJ, Naeve GS, Lee AS (1993) Temporal regulation of cyclin A-p107 and p33cdk2 complexes binding to a human thymidine kinase promoter element important for G1-S phase transcriptional regulation. Proc Natl Acad Sci USA 90:3554–3558

    Article  PubMed  CAS  Google Scholar 

  33. Guadagno TM, Newport JW (1996) Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell 84:73–82

    Article  PubMed  CAS  Google Scholar 

  34. Thornton BR, Toczyski DP (2003) Securin and B-cyclin/CDK are the only essential targets of the APC. Nat Cell Biol 5:1090–1094

    Article  PubMed  CAS  Google Scholar 

  35. Pietenpol JA, Stewart ZA (2002) Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 181–182:475–481

    Article  PubMed  Google Scholar 

  36. Nagy Z (2000) Cell cycle regulatory failure in neurones: causes and consequences. Neurobiol Aging 21:761–769

    Article  PubMed  CAS  Google Scholar 

  37. DeGregori J, Johnson DG (2006) Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr Mol Med 6:739–748

    PubMed  CAS  Google Scholar 

  38. Liu DX, Biswas SC, Greene LA (2004) B-myb and C-myb play required roles in neuronal apoptosis evoked by nerve growth factor deprivation and DNA damage. J Neurosci 24:8720–8725

    Article  PubMed  CAS  Google Scholar 

  39. Nahle Z, Polakoff J, Davuluri RV et al (2002) Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 4:859–864

    Article  PubMed  CAS  Google Scholar 

  40. Nguyen MD, Boudreau M, Kriz J et al (2003) Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci 23:2131–2140

    PubMed  CAS  Google Scholar 

  41. Lee MH, Nikolic M, Baptista CA et al (1996) The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. Proc Natl Acad Sci USA 93:3259–3263

    Article  PubMed  CAS  Google Scholar 

  42. Akashiba H, Matsuki N, Nishiyama N (2006) p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study. Cell Mol Life Sci 63:2397–2404

    Article  PubMed  CAS  Google Scholar 

  43. Newcomb EW, Tamasdan C, Entzminger Y et al (2004) Flavopiridol inhibits the growth of GL261 gliomas in vivo: implications for malignant glioma therapy. Cell Cycle 3:230–234

    PubMed  CAS  Google Scholar 

  44. Swanton C (2004) Cell-cycle targeted therapies. Lancet Oncol 5:27–36

    Article  PubMed  CAS  Google Scholar 

  45. Dai Y, Grant S (2004) Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. Curr Oncol Rep 6:123–130

    Article  PubMed  Google Scholar 

  46. Meijer L, Raymond E (2003) Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res 36:417–425

    Article  PubMed  CAS  Google Scholar 

  47. Abraham RT, Acquarone M, Andersen A et al (1995) Cellular effects of olomoucine, an inhibitor of cyclin-dependent kinases. Biol Cell 83:105–120

    Article  PubMed  CAS  Google Scholar 

  48. Kranenburg O, van der Eb AJ, Zantema A (1996) Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Embo J 15:46–54

    PubMed  CAS  Google Scholar 

  49. Bossenmeyer-Pourie C, Chihab R, Schroeder H et al (1999) Transient hypoxia may lead to neuronal proliferation in the developing mammalian brain: from apoptosis to cell cycle completion. Neuroscience 91:221–231

    Article  PubMed  CAS  Google Scholar 

  50. Park DS, Morris EJ, Bremner R et al (2000) Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J Neurosci 20:3104–3114

    PubMed  CAS  Google Scholar 

  51. Jorda EG, Verdaguer E, Canudas AM et al (2003) Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology 45:672–683

    Article  PubMed  CAS  Google Scholar 

  52. Rashidian J, Iyirhiaro G, Aleyasin H et al (2005) Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci USA 102:14080–14085

    Article  PubMed  CAS  Google Scholar 

  53. Becker EB, Bonni A (2004) Cell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol 72:1–25

    Article  PubMed  CAS  Google Scholar 

  54. Takuma K, Baba A, Matsuda T (2004) Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol 72:111–127

    Article  PubMed  CAS  Google Scholar 

  55. Zhu Z, Zhang Q, Yu Z et al (2007) Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo. Glia 55:546–558

    Article  PubMed  Google Scholar 

  56. Koguchi K, Nakatsuji Y, Okuno T et al (2003) Microglial cell cycle-associated proteins control microglial proliferation in vivo and in vitro and are regulated by GM-CSF and density-dependent inhibition. J Neurosci Res 74:898–905

    Article  PubMed  CAS  Google Scholar 

  57. Yamada J, Sawada M, Nakanishi H (2006) Cell cycle-dependent regulation of kainate-induced inward currents in microglia. Biochem Biophys Res Commun 349:913–919

    Article  PubMed  CAS  Google Scholar 

  58. Nakatsuji Y, Miller RH (2001) Density dependent modulation of cell cycle protein expression in astrocytes. J Neurosci Res 66:487–496

    Article  PubMed  CAS  Google Scholar 

  59. Mirjany M, Ho L, Pasinetti GM (2002) Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J Pharmacol Exp Ther 301:494–500

    Article  PubMed  CAS  Google Scholar 

  60. Ino H, Chiba T (2001) Cyclin-dependent kinase 4 and cyclin D1 are required for excitotoxin-induced neuronal cell death in vivo. J Neurosci 21:6086–6094

    PubMed  CAS  Google Scholar 

  61. Small DL, Monette R, Fournier MC et al (2001) Characterization of cyclin D1 expression in a rat global model of cerebral ischemia. Brain Res 900:26–37

    Article  PubMed  CAS  Google Scholar 

  62. van Lookeren Campagne M, Gill R (1998) Cell cycle-related gene expression in the adult rat brain: selective induction of cyclin G1 and p21WAF1/CIP1 in neurons following focal cerebral ischemia. Neuroscience 84:1097–1112

    Article  PubMed  Google Scholar 

  63. Faden AI, Movsesyan VA, Knoblach SM et al (2005) Neuroprotective effects of novel small peptides in vitro and after brain injury. Neuropharmacology 49:410–424

    Article  PubMed  CAS  Google Scholar 

  64. Kang SK, So HH, Moon YS et al (2006) Proteomic analysis of injured spinal cord tissue proteins using 2-DE and MALDI-TOF MS. Proteomics 6:2797–2812

    Article  PubMed  CAS  Google Scholar 

  65. Velardo MJ, Burger C, Williams PR et al (2004) Patterns of gene expression reveal a temporally orchestrated wound healing response in the injured spinal cord. J Neurosci 24:8562–8576

    Article  PubMed  CAS  Google Scholar 

  66. Kobori N, Clifton GL, Dash P (2002) Altered expression of novel genes in the cerebral cortex following experimental brain injury. Brain Res Mol Brain Res 104:148–158

    Article  PubMed  CAS  Google Scholar 

  67. Katano H, Masago A, Taki H et al (2000) p53-independent transient p21(WAF1/CIP1) mRNA induction in the rat brain following experimental traumatic injury. Neuroreport 11:2073–2078

    Article  PubMed  CAS  Google Scholar 

  68. Tanaka H, Yamashita T, Yachi K et al (2004) Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience 127:155–164

    Article  PubMed  CAS  Google Scholar 

  69. Hoke A, Silver J (1994) Heterogeneity among astrocytes in reactive gliosis. Perspect Dev Neurobiol 2:269–274

    PubMed  CAS  Google Scholar 

  70. Ridet JL, Malhotra SK, Privat A et al (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577

    Article  PubMed  CAS  Google Scholar 

  71. Davies SJ, Field PM, Raisman G (1996) Regeneration of cut adult axons fails even in the presence of continuous aligned glial pathways. Exp Neurol 142:203–216

    Article  PubMed  CAS  Google Scholar 

  72. Faulkner JR, Herrmann JE, Woo MJ et al (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155

    Article  PubMed  CAS  Google Scholar 

  73. McGraw J, Hiebert GW, Steeves JD (2001) Modulating astrogliosis after neurotrauma. J Neurosci Res 63:109–115

    Article  PubMed  CAS  Google Scholar 

  74. Tian DS, Yu ZY, Xie MJ et al (2006) Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine. J Neurosci Res 84:1053–1063

    Article  PubMed  CAS  Google Scholar 

  75. Iannotti C, Ping Zhang Y, Shields CB et al (2004) A neuroprotective role of glial cell line-derived neurotrophic factor following moderate spinal cord contusion injury. Exp Neurol 189:317–332

    Article  PubMed  CAS  Google Scholar 

  76. Burns KA, Ayoub AE, Breunig JJ et al (2007) Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia-hypoxia. Cereb Cortex

  77. Kuan CY, Schloemer AJ, Lu A et al (2004) Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. J Neurosci 24:10763–10772

    Article  PubMed  CAS  Google Scholar 

  78. Sakurai M, Hayashi T, Abe K et al (2000) Cyclin D1 and Cdk4 protein induction in motor neurons after transient spinal cord ischemia in rabbits. Stroke 31:200–207

    PubMed  CAS  Google Scholar 

  79. Cicero S, Herrup K (2005) Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci 25:9658–9668

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neuroscience, Georgetown University Medical Center, Room EP16A, New Research Building, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA

    Kimberly R. Byrnes & Alan I. Faden

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  1. Kimberly R. Byrnes
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  2. Alan I. Faden
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Correspondence to Kimberly R. Byrnes.

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Special issue dedicated to Dr. Moussa Youdim.

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Byrnes, K.R., Faden, A.I. Role of Cell Cycle Proteins in CNS Injury. Neurochem Res 32, 1799–1807 (2007). https://doi.org/10.1007/s11064-007-9312-2

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